NY State Institute for Basic Research in Developmental Disabilities

New York City, NY, United States

NY State Institute for Basic Research in Developmental Disabilities

New York City, NY, United States
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Gilbert M.E.,U.S. Environmental Protection Agency | Ramos R.L.,New York Institute of Technology | Mccloskey D.P.,CUNY - College of Staten Island | Goodman J.H.,NY State Institute for Basic Research in Developmental Disabilities | Goodman J.H.,SUNY Downstate Medical Center
Journal of Neuroendocrinology | Year: 2014

Thyroid hormones (TH) play crucial roles in brain maturation and are important for neuronal migration and neocortical lamination. Subcortical band heterotopia (SBH) represent a class of neuronal migration errors in humans that are often associated with childhood epilepsy. We have previously reported the presence of SBH in a rodent model of low level hypothyroidism induced by maternal exposure to the goitrogen, propylthiouracil (PTU). In the present study, we report the dose-response characteristics of this developmental malformation and the connectivity of heterotopic neurones with other brain regions, as well as their functionality. Pregnant rats were exposed to varying concentrations of PTU through the drinking water (0-10 p.p.m.) beginning on gestational day 6 to produce graded levels of TH insufficiency. Dose-dependent increases in the volume of the SBH present in the corpus callosum were documented in the adult offspring, with a clear presence at concentrations of PTU that resulted in minor (< 15%) reductions in maternal serum thyroxine as measured when pups were weaned. SBH contain neurones, oligodendrocytes, astrocytes and microglia. Monoaminergic and cholinergic processes were prevalent and many of the axons were myelinated. Anatomical connectivity of SBH neurones to cortical neurones and the synaptic functionality of these anatomical connections was verified by ex vivo field potential recordings. SBH persisted in adult offspring despite a return to euthyroid status on termination of exposure and these offspring displayed an increased sensitivity to seizures. Features of this model are attractive with respect to the investigation of the molecular mechanisms of cortical development, the effectiveness of therapeutic intervention in hypothyroxinaemia during pregnancy and the impact of the very modest TH imbalance that accompanies exposure to environmental contaminants. © Published 2014. This article is a U.S. Government work and is in the public domain in the USA.


Li X.,NY State Institute for Basic Research in Developmental Disabilities | Hyink D.,Mount Sinai School of Medicine | Wilson P.D.,University College London
Developmental Biology | Year: 2011

Angiogenesis is a fundamental step in several important physiological events and pathological conditions including embryonic development, wound repair, tumor growth and metastasis. PRKX was identified as a novel type-I cAMP-dependent protein kinase gene expressed in multiple developing tissues. PRKX has also been shown to be phylogenetically and functionally distinct from PKA. This study presents the first evidence that PRKX stimulates endothelial cell proliferation, migration, and vascular-like structure formation, which are the three essential processes for angiogenesis. In contrast, classic PKA demonstrated an inhibitory effect on endothelia vascular-like structure formation. Our findings suggest that PRKX is an important protein kinase engaged in the regulation of angiogenesis and could play critical roles in various physiological and pathological conditions involving angiogenesis. PRKX binds to Pin-1, Magi-1 and Bag-3, which regulate cell proliferation, apoptosis, differentiation and tumorigenesis. The interaction of PRKX with Pin-1, Magi-1 and Bag-3 could contribute to the stimulating role of PRKX in angiogenesis. © 2011.


Wei H.,Shanxi Medical University | Alberts I.,LaGuardia CC CUNY | Li X.,NY State Institute for Basic Research in Developmental Disabilities
Neuroscience | Year: 2013

Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction, deficits in verbal and non-verbal communication, and repetitive behavior and restricted interests. Emerging evidence suggests that aberrant neuroimmune responses may contribute to phenotypic deficits and could be appropriate targets for pharmacologic intervention. Interleukin (IL)-6, one of the most important neuroimmune factors, has been shown to be involved in physiological brain development and in several neurological disorders. For instance, findings from postmortem and animal studies suggest that brain IL-6 is an important mediator of autism-like behaviors. In this review, a possible pathological mechanism behind autism is proposed, which suggests that IL-6 elevation in the brain, caused by the activated glia and/or maternal immune activation, could be an important inflammatory cytokine response involved in the mediation of autism-like behaviors through impairments of neuroanatomical structures and neuronal plasticity. Further studies to investigate whether IL-6 could be used for therapeutic interventions in autism would be of great significance. © 2013 IBRO.


Jiao D.,Shanghai JiaoTong University | Liu Y.,Shanghai JiaoTong University | Li X.,NY State Institute for Basic Research in Developmental Disabilities | Liu J.,CAS Shanghai Institute of Materia Medica | Zhao M.,Shanghai JiaoTong University
Frontiers in Cellular Neuroscience | Year: 2015

Abuse of amphetamine-type stimulants (ATS) has become a global public health problem. ATS causes severe neurotoxicity, which could lead to addiction and could induce psychotic disorders or cognitive dysfunctions. However, until now, there has been a lack of effective medicines for treating ATS-related problems. Findings from recent studies indicate that in addition to the traditional dopamine-ergic system, the GABA (gamma-aminobutyric acid)-ergic system plays an important role in ATS abuse. However, the exact mechanisms of the GABA-ergic system in amphetamine-type stimulant use disorders are not fully understood. This review discusses the role of the GABA-ergic system in ATS use disorders, including ATS induced psychotic disorders and cognitive dysfunctions. We conclude that the GABA-ergic system are importantly involved in the development of ATS use disorders through multiple pathways, and that therapies or medicines that target specific members of the GABA-ergic system may be novel effective interventions for the treatment of ATS use disorders. © 2015 Jiao, Liu, Li, Liu and Zhao.


Cheng P.,Shanghai JiaoTong University | Alberts I.,City University of New York | Li X.,NY State Institute for Basic Research in Developmental Disabilities
International Journal of Developmental Neuroscience | Year: 2013

Extracellular signal regulated kinases (ERK) are important components of the Ras-Raf-MEK-ERK signaling pathway cascades that mediate intracellular stimuli transduction and gene expression. ERK1 (44. kDa) and ERK2 (42. kDa) are homologous subtypes of the ERK family, which participate in regulation of a variety of cell activities, including cell proliferation, migration and differentiation, especially in the central nervous systerm (CNS). Hence, they exert critical effects on neuron and astrocyte development. Astrocytes are critically involved in maintaining CNS homeostasis and supporting neuron growth. When exposed to an extracellular stimulus, such as inflammation or oxidative stress, the corresponding cell response can be regulated by the ERK1/2 signaling pathway. Furthermore, several lines of evidence have demonstrated a correlation between astrocyte activity and the Ras-Raf-MEK-ERK signaling pathway. However many questions remain unanswered regarding the role of ERK1/2 in astrocyte development. This review summarizes the possible role of ERK1/2 signaling cascades in modulating the proliferation, differentiation and apoptosis of astrocytes in both physiological and pathological conditions. In addition, this review also briefly elucidates the participation of ERK1/2 in the process of human brain glia tumor oncogenesis and metastasis, which will provide some concepts for treatment strategies to delay the process of tumor evolution. © 2013 ISDN.


Wei H.,NY State Institute for Basic Research in Developmental Disabilities | Wei H.,Shanghai JiaoTong University | Chadman K.K.,NY State Institute for Basic Research in Developmental Disabilities | McCloskey D.P.,CUNY - College of Staten Island | And 4 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2012

Abnormal immune responses have been reported to be associated with autism. A number of studies showed that cytokines were increased in the blood, brain, and cerebrospinal fluid of autistic subjects. Elevated IL-6 in autistic brain has been a consistent finding. However, the mechanisms by which IL-6 may be involved in the pathogenesis of autism are not well understood. Here we show that mice with elevated IL-6 in the brain display many autistic features, including impaired cognitive abilities, deficits in learning, abnormal anxiety traits and habituations, as well as decreased social interactions. IL-6 elevation caused alterations in excitatory and inhibitory synaptic formations and disrupted the balance of excitatory/inhibitory synaptic transmissions. IL-6 elevation also resulted in an abnormal change in the shape, length and distributing pattern of dendritic spines. These findings suggest that IL-6 elevation in the brain could mediate autistic-like behaviors, possibly through the imbalances of neural circuitry and impairments of synaptic plasticity. © 2012.


Wei H.,Shanxi Medical University | Alberts I.,LaGuardia CC | Li X.,NY State Institute for Basic Research in Developmental Disabilities
International Journal of Developmental Neuroscience | Year: 2014

Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction, deficits in verbal and non-verbal communication, and repetitive behavior and restricted interests. The normal brain development during fetal brain development and the first year of life is critical to the behaviors and cognitions in adulthood. Programmed cell death (apoptosis) is an important mechanism that determines the size and shape of the brain and regulates the proper wiring of developing neuronal networks. Pathological activation of apoptotic death pathways under pathological conditions may lead to neuroanatomic abnormalities and possibly to developmental disabilities. It has been demonstrated a possible association between neural cell death and autism. Here, the abnormal apoptosis found in autism from postmortem and animal studies was reviewed and the possible mechanism was discussed. © 2014 ISDN.


Wei H.,Shanxi Provincial Peoples Hospital | Mori S.,Johns Hopkins University | Hua K.,Johns Hopkins University | Li X.,NY State Institute for Basic Research in Developmental Disabilities
International Journal of Developmental Neuroscience | Year: 2012

Abnormal neuroimmune responses have been reported to be associated with autism and could be appropriate targets for pharmacologic intervention. Our previous studies showed that neuroimmune factor, interleukin (IL)-6, was significantly elevated in the fontal cortex and cerebellum of autistic subjects. The IL-6 overexpressing mice displayed several autism-like features as well as an abnormal dendritic spine morphology and synaptic function. The purpose of this study was to examine the volumetric differences in the brain of IL-6 overexpressing mice and compare with corresponding control mice using magnetic resonance imaging. Here we show that IL-6 overexpressing mice display an increase in the total brain volume. In addition, the lateral ventricle is also enlarged in the IL-6 overexpressing mice. The brain structures surrounding the lateral ventricle were squeezed and deformed from the normal location. These results indicate that IL-6 elevation in the brain could mediate neuroanatomical abnormalities. Taking together with our previous findings, a mechanism by which IL-6 may be involved in the pathogenesis of autism is proposed. © 2012 ISDN.


Li X.,NY State Institute for Basic Research in Developmental Disabilities
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2011

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by renal cyst formation and caused by mutations in the PKD1 and PKD2 genes, which encode polycystin-1(PC-1) and -2 (PC-2) proteins, respectively. PC-1 is a large plasma membrane receptor involved in the regulation of several biological functions and signaling pathways including the Wnt cascade, AP-1, PI3kinase/Akt, GSK3β, STAT6, Calcineurin/NFAT and the ERK and mTOR cascades. PC-2 is a calcium channel of the TRP family. The two proteins form a functional complex and prevent cyst formation, but the precise mechanism(s) involved remains unknown. © 2011.


Xu N.,Hunan Childrens Hospital | Li X.,NY State Institute for Basic Research in Developmental Disabilities | Zhong Y.,Hunan Childrens Hospital
Mediators of Inflammation | Year: 2015

Autism is a disorder of neurobiological origin characterized by problems in communication and social skills and repetitive behavior. After more than six decades of research, the etiology of autism remains unknown, and no biomarkers have been proven to be characteristic of autism. A number of studies have shown that the cytokine levels in the blood, brain, and cerebrospinal fluid (CSF) of autistic subjects differ from that of healthy individuals; for example, a series of studies suggests that interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) are significantly elevated in different tissues in autistic subjects. However, the expression of some cytokines, such as IL-1, IL-2, transforming growth factor-β (TGF-β), and granulocyte-macrophage colony-stimulating factor (GM-CSF), is controversial, and different studies have found various results in different tissues. In this review, we focused on several types of proinflammatory and anti-inflammatory cytokines that might affect different cell signal pathways and play a role in the pathophysiological mechanism of autistic spectrum disorders. © 2015 Ningan Xu et al.

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